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The Barbara Davis Center (with Children’s Hospital Colorado for inpatient pediatric diabetes care) follows 3,000 children and 2,000 adults with Type 1 diabetes. For the great majority, Type 1 diabetes is an autoimmune disease. We can now predict the development of Type 1 diabetes, prevent it in animal models and trials for prevention in man are underway.
The Center has pioneered the prediction of Type 1 diabetes, developing and using autoantibody assays targeting four major islet autoantigens (GAD65, IA-2, insulin, and most recently ZnT8). Given genetic susceptibility primarily determined by HLA alleles, individuals in the general population as well as relatives who express >=2 of the above autoantibodies progress to diabetes. Though autoantibodies are used for diagnosis of autoimmune diabetes and prediction of the disease, T cells cause the disease by killing cells in islets that produce insulin.
Studies of the NOD mouse model indicates that insulin is the primary target, and mutating a single amino acid of insulin peptide B:9-23, prevents diabetes (Nakayama et al, Nature 2005). Major studies are directed at a trimolecular complex of HLA presenting molecule, insulin peptide, recognized by specific T cell receptors, which underlies disease pathogenesis. Structural characterization of trimolecular complexes targeting insulin peptides for man and mouse is being pursued to develop both T cell disease related biomarkers and develop specific immunotherapy.